Cited by 23RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryLipid Membrane Structure and Behavior

The DOI matches its Crossref record; 63 of the 64 references it cites were found in a registry or an index, and 1 are not checked yet.

Computational Design and Experimental Characterization of Peptides Intended for pH-Dependent Membrane Insertion and Pore Formation

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Abstract

There are many opportunities to use macromolecules, such as peptides and oligonucleotides, for intracellular applications. Despite this, general methods for delivering these molecules to the cytosol in a safe and efficient manner are not available. Efforts to develop a variety of intracellular drug delivery systems such as viral vectors, lipoplexes, nanoparticles, and amphiphilic peptides have been made, but various challenges such as delivery efficiency, toxicity, and controllability remain. A central challenge is the ability to selectively perturb, not destroy, the membrane to facilitate cargo introduction. Herein, we describe our efforts to design and characterize peptides that form pores inside membranes at acidic pH, so-called pH-switchable pore formation (PSPF) peptides, as a potential means for facilitating cargo translocation through membranes. Consistent with pore formation, these peptides exhibit low-pH-triggered selective release of ATP and miRNA, but not hemoglobin, from red blood cells. Consistent with these observations, biophysical studies (tryptophan fluorescence, circular dichroism, size-exclusion chromatography, analytical ultracentrifugation, and attenuated total reflectance Fourier transformed infrared spectroscopy) show that decreased pH destabilizes the PSPF peptides in aqueous systems while promoting their membrane insertion. Together, these results suggest that reduced pH drives insertion of PSPF peptides into membranes, leading to target-specific escape through a proposed pore formation mechanism.

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  • Achieving the desired balance between multiple target coiled-coil states often requires several rounds of trial-and-error and a detailed understanding of the energetic factors that discriminate between alternative topologies and oligomerization states.

    “While this has been accomplished in a number of cases,18−31 achieving the desired balance between multiple target coiled-coil states often requires several rounds of trial-and-error and a detailed understanding of the energetic factors that discriminate between alternative topologies and oligomerization states.”

    From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [23]

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Authors
Zhang, Y., Bartz, R., Grigoryan, G., Bryant, M., Aaronson, J., Beck, S., Innocent, N., Klein, L., Procopio, W., Tucker, T., Jadhav, V., Tellers, D. M., & DeGrado, W. F.
Affiliations
  • University of Pennsylvania (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • University of California, San Francisco (US)
Corresponding author
  • Tellers, David M.
  • DeGrado, William F.
Venue
ACS Chemical Biology
Published
2015-01-28
Volume
10
Issue
4
Pages
1082-1093
ISSN
  • 1554-8929 (ISSN-L)
  • 1554-8937
OpenAlex
W2086480986
Cited by
23
References
64
Citations by year
2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 1 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 6 · 2015: 3
FWCI
1.88
Type
journal article
Language
en
Open access
Locations
  • ACS Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institute of General Medical Sciences (R01GM054616)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
membrane insertion, intracellular drug delivery, ATP release, erythrocytes, cytosolic delivery
MeSH terms
Adenosine Triphosphate, Amino Acid Sequence, Cell Membrane, Chromatography, Gel, Circular Dichroism, Erythrocytes, Hemolysis, Humans, Hydrogen-Ion Concentration, Lipid Bilayers, Molecular Sequence Data, Peptides, Solubility, Spectrometry, Fluorescence, Tryptophan, Drug Design, Protein Engineering, MicroRNAs

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